Despite the importance of the indigenous microflora of the large intestine to human health and disease, the mechanisms which control its composition are unknown, because (a) experimental models used in the past were inadequate, and (b) the flora is controlled by the interplay of numerous control mechanisms. Consequently, studies of single mechanisms cannot yield an understanding of the whole. We plan to overcome these shortcomings (a) by using continuous flow (CF) cultures of mouse cecal flora, as well as conventional mice as experimental models, and (b) by constructing mathematical models of the interplay among ecologic control mechanisms. A major part of the proposed project is to test a hypothesis generated by an earlier mathematical model namely, that bacterial adhesion in the large intestine is not necessary for colonization of the large intestine, but is required to maintain the stability of the flora. We plan to identify a number of strains of indigenous species (E. coli, Bacteroides sp., Fusobacterium sp., Eubacterium sp.) as to their ability to (a) adhere to epithelial cells, (b) adhere to the surfaces of other indigenous bacteria that are constituents of the surface layers of the large gut, (c) associate with the mucus gel, or (d) adhere poorly to any of these structures. The ability of these strains to colonize mice or CF cultures will be tested. The mathematical model will be improved as necessary, until it is able to closely simulate the observed population dynamics. Throughout the study we will maintain a continuous interplay between experimental and mathematical approaches. In addition to the above studies, we plan to expand our present mathematical model of plasmid transfers in the large intestine. This model currently is based on the assumption of interactions occurring among freely suspended bacteria. We will use the data on adhesion in the gut and in CF cultures generated in the above described work to model plasmid transfer among adherent bacterial populations. We expect eventually to produce a combined mathematical model which can account for plasmid transfer among adherent as well as suspended bacterial populations in the large intestine.